Genetic and neuropsychological studies have each made important contributions to the understanding of schizophrenia. Family, twin and adoption studies provide strong support for a genetic component in the etiology and schizophrenia, and neurodiagnostic approaches strongly indicate the presence of brain dysfunction in many schizophrenics. Moreover, variability in the occurrence of mental illness in the relatives of schizophrenics and variability in the types and severity of structural, physiological and functional abnormalities suggests significant genetic and neuropsychological heterogeneity within schizophrenia. Linking these two research domains thus represents a crucial step toward elucidating the heterogeneity of schizophrenia. This proposal is for a unified investigation of genetic and neuropsychological heterogeneity in schizophrenia with the goal of determining whether specific types of neuropsychological deficits reflect familial or nonfamilial etiological factors. Using the family study method, the proposed research plan is to diagnose psychiatric hospital patients and normal controls, and their first degree relatives using structured psychiatric interviews, and to assess all of these individuals with a comprehensive neuropsychological battery. Genetic heterogeneity will be assessed by dividing schizophrenics into familial and nonfamilial subgroups defined on the basis of the family study. Specificity of neuropsychological deficits to familial and nonfamilial schizophrenia will be assessed by comparing the schizophrenic subgroups to bipolar and normal control groups. The study will compare the ability of seven different models of schizophrenia to account for the patterns of neuropsychological variability among the schizophrenic groups and their relatives. The results will also be used to determine the heritability of neuropsychological deficits, to determine which measures may be vulnerability markers for schizophrenia, and to study neuropsychological impairment as an alternative schizophrenic phenotype for use in segregation analyses. By elucidating the genetic and neuropsychological heterogeneity of schizophrenia, the proposed study will clarify underlying mechanisms and aid in the development of homogeneous subgroups that will be informative for future etiological and pathophysiological research. The delineation of neuropsychological profiles and familial and nonfamilial forms of schizophrenia will contribute to psychiatric genetic counseling and to the development of treatment-relevant subgroups.